Process for substituted cyclohexenes

ABSTRACT

The present invention relates to a process for 3r-N-Monomethylamino-4 cis-phenyl-4 trans-ethoxycarbonyl-cyclohexene and its N-substitution products which are generally useful as analgesics.

This is a division of application Ser. No. 117,142, now U.S. Pat. No.3,792,080, filed Feb. 19, 1971.

The present invention relates to a process for the production of3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1) (I) andits N-substitution products of the general formula II ##SPC1##

where R represents a lower alkyl, aralkyl, or alkenyl radical, asubstituted lower alkyl or an acyl group, the term "lower alkyl radical"meaning a hydrocarbon radical having 1 to 7 C atoms arranged in astraight or branched chain, the term including radicals such as ethyl,propyl, isopropyl, etc. With the "lower substituted alkyl radical" adi-lower-alkyl-amino group has been substituted for a hydrogen atom, inaddition; the two lower alkyl radicals may be linked to form a ringeither with or without intervention of a heteroatom. The term "aralkyl"means a lower alkyl radical where the phenyl group has been substitutedfor an H-atom, such as benzyl and phenethyl. The term "alkenyl"signifies an unsaturated hydrocarbon having 3 to 5 C atoms. For thepurpose of this specification acid radicals of the category ofsubstituted or non-substituted lower alkane carboxylic acids, aromaticcarboxylic acids and carbamic acids, such as acetyl, propionyl,succinoyl, oxalyl, maleyl, benzoyl, aminobenzoyl, chlorobenzoyl,carbamyl, ethylcarbamyl etc, are termed "acyl groups".

This invention also comprises acid addition or quarternary compounds ofsuch products I and II which are capable of forming salts withnon-toxic, pharmaceutically acceptable acids or alkyl halides.

Compounds I and II of the invention exhibit considerable analgesic andanti-inflammatory activity in mammals such as mice, rats, dogs etc., asnormally used in pharmacological tests. Therapeutic application of thesecompounds is indicated in use of pain all kinds. The dose required forremoving pain is between 5 and 50 mg/kg body weight.

For pharmaceutical use the products of the invention may, when providedwith the usual galenic additives, be processed into dosage forms ofmedical benefit, such as tablets, capsules, ampoules etc.

Compounds II of the invention are prepared by way of I from3r-N,N-dimethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1) (III);preparation of III has been described in my U.S. Pat. No. 3,577,127,issued Jan. 19, 1971.

1. It has now been found, most surprisingly, that 3r-N- ##SPC2##

monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1) (I), acompound which owing to its strong analgesic activity is ofpharmaceutical interest as such and is used as the starting material forthe preparation of substances II, can be produced in a most simple wayby bromination of III in a carbon chloride, preferably in chloroform, at-15° to 0°C, advantageously at -10°C, and subsequent treatment withwater. This reaction is all the more remarkable as it runs withoutaddition of any bromine to the cyclohexene double bond, without allylbromination and without substitution of the phenyl nucleus.Conventional, multistage de-alkylation procedures like von Braundegradation or degradation by means of acylating agents were found tofail in the preparation of I, resulting merely in an unidentifiablemixture of secondary products. Furthermore preparation of I out of IIIin small yields is possible by means of oxidation of II with Hg^(II)-acetate in aqueous acetic acid at elevated temperatures, preferably theboiling point of 10% acetic acid, and by oxidation of III with gaseousoxygen in the presence of noble metal catalysts, preferably PtO₂, in aninert solvent, advantageously in benzene.

2. Compound I can be reacted with alkyl halides, acyl halides,aminoalkyl halides, and isocyanates. These reactions are bestillustrated by the following reaction chart: ##SPC3##

where the groups R₁, R₂ CO, and R₃ NH.CO represent a lower, substitutedor non-substituted alkyl or alkenyl radical, an acyl radical, or acarbamic acid radical, as defined above.

These known reactions of secondary amines, require a special workingtechnique, owing to the low basicity and the enormous steric hindranceof the N-atom, on the one hand, and the sensitivity of I, on the otherhand. For the alkylation reactions in the presence or absence of asolvent, this means that reaction is forced, by using at least anequimolar amount of N-ethyldiisopropylamine as the condensation agent,and observing a temperature range of 70°-130°C. Acylations are alsoperformed by means of this amine or - which is less effective - bytriethylamine. This preferred temperature range is between 0° and 100°C.Aromatic hydrocarbons, toluene in particular, have proved to be suitablesolvents. Reactions with anhydrides can be achieved by a melting processor in DMF-solution, a temperature range of 120°-140°C having to beobserved. Acylation with isocyanates is performed in an ether at15°-50°C, preferably in dioxane at 30°C. Free cyanic acid in aqueousacetic acid at 70°C adds to the NH group of I.

The following examples are given to illustrate the invention.

1. 3r-N-Monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1) (I)

1.1 To a well stirred solution of 273.3 g. (1 mole) of III in 0.5 l. ofchloroform 159.8 g. (1 mole) of bromine dissolved in 250 cc. ofchloroform are added dropwise at -10°C within 90 min. Stirring iscontinued for 30 min. at -10°C. The solution is poured into 4 l. ofwater, and the phases are stirred for 5 hours at room temperature. Themixture is rendered alkaline with aqueous ammonia, the organic phase iswashed twice with water, dried over MgSO₄ and evaporated; the residue istaken up in ethyl acetate, and the hydrochloride of I is precipitated bya solution of hydrogen chloride in ethyl acetate. The product isanalytically pure. M.P.: 218°-219°C. It can be recrystallized from amixture of ethyl acetate and isopropanol. The free base melting between39.5 and 40.5° C is prepared by alkalizing with aqueous NaOH.

Yield: 320 g. (62% as hydrochloride) C₁₆ H₂₂ ClNO₂ (295.9)

Calculated: C 64.94; H 7.50; N 4.73; Cl11.98; Found: C 64.74; H 7.36; N4.82; Cl 12.34.

1.2 108 g. (0.4 mole) of III are dissolved in 1 l. of 10% acetic acid;then a solution of 505 g. (1.6 moles) of Hg^(II) -acetate in 2 l. of 10%acetic acid is added and the mixture heated to boiling for 2 hours. Theprecipitated Hg^(I) salt is separated, and the filtrate alkalized with 2N sodium hydroxide solution. The oily portion is taken up in ether; theethereal phase is evaporated and the residue extracted with petroleumether. Following evaporation of the solvent, the residue is taken up inethyl acetate and converted into the hydrochloride as described above.

Yield: 24.0 g. (23.5% of theory) M.P. 212°-213°C.

1.3 13.6 g. (0.05 mole) of III are dissolved in 100 ml. benzene. To thissolution 2 g. of PtO₂ are added, and the mixture is shaken withoutpressure in an O₂ atmosphere for 8 days. After filtrating, the benzenephase is extracted with 2 N acetic acid and the aqueous layer alkalizedwith 2 N NaOH. The oil which has separated is taken up in ethyl acetateand converted into the hydrochloride according to 1.2 M.P. 212°-213°C.

Yield: 0.6 g. (4.7%)

2.3r-(N-Methyl-N-ethyl-amino)-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

51.8 g. (0.2 mole) of3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1) (I) areadded to 35 g. of diethyl sulfate and 45 g. of N-ethyl-diisopropylaminewithin 1 h. at 100°C. Subsequently the mixture is heated for another 2hrs. to 125°-130°C. After cooling, it is mixed with a solution of 0.3mole of KOH in 30 cc. of water, with stirring, and the separated aqueousphase is extracted with ether. The combined organic layers are dried andfreed from ether and amine. The residue is taken up in ethyl acetate.Any starting substance not transformed is precipitated by addition of200 ml. of a saturated ethereal oxalic acid solution.

From the filtrate, 2 is precipitated as naphthalene-1,5-disulfonate

Yield: 40.0 g. (47%) from isopropanol. M.P. 171°-173°C. C₄₆ H₅₈ N₂ O₁₀S₂ (863.12)

Calculated: C 64.01; H 6.77; N 3.25; S 7.44; Found: C 64.31; H 6.68; N3.18; S 7.15.

3.3r-(N-Methyl-N-allyl-amino)-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

25.9 g. (0.1 mole) of I together with 16 g. of allyl bromide and 22 g.of ethyldiisopropylamine, are heated for 1 h. to 90°C. After cooling,the product is taken up in ether and filtered, the ethereal phase beingwashed with water and dried over potassium carbonate. The residue of theethereal phase (at 12 torr, 100°C) is dissolved in isopropanol, asolution of naphthalene-1,5-disulfonic acid in isopropanol being added.The naphthalene-1,5-disulfonate of 3 precipitates.

Yield: 26.2 g. (30%) from isopropanol. M.P. 182°-185°C. C₄₈ H₅₈ N₂ O₁₀S₂ (887.1)

Calculated: C 64.98; H 6.60; N 3.16; S 7.22; Found: C 65.20; H 6.55; N3.24; S 7.13.

4.3r-(N-Methyl-N-phenethylamino)-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

51.8 g. (0.2 mole) of I, 45 g. of β-phenethylbromide, and 55 g. ofN-ethyldiisopropylamine are dissolved in 300 cc. of dimethylsulfoxideand heated for 3 hrs. to 100°C. This solution is introduced into 1 l. ofwater; following extraction with toluene the organic phase is evaporatedto dryness under vacuum. The residue is taken up in ethyl acetate andfreed from the starting material as in example 2. By evaporation andalkalization with 2 N NaOH the base according to 4. is freed. It isprecipitated as naphthalene-1,5-disulfonate when dissolved inisopropanol as in example.

Yield: 15 g. (31%) from a mixture of ethanol and isopropanol. M.P.172°-173°C. C₅₈ H₆₆ N₂ O₁₀ S₂ (1015.32)

Calculated: C 68.61; H 6.55; N 2.76; S 6.31; Found: C 68.44; H 6.65; N2.70; S 6.43.

5.3r-(N-methyl-N-β-morpholinoethyl-amino)-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

25.9 g. (0.1 mole) of I and 0.1 mole of freshly preparedN-(2-chloroethyl)-morpholine are dissolved in 100 cc. ofdimethyl-sulfoxide and, together with 35 g. ofN-ethyl-diisopropyl-amine, heated for 6 hrs. to 100°C. The product istaken up in toluene; the organic phase is thoroughly washed with water,dried over K₂ CO₃ and evaporated. The product of 5 is obtained asoxalate upon addition of an ethyl acetate solution of oxalic acid to thesolution of the residue in ethyl acetate.

Yield: 9 g. (18%) from acetonitrile. M.P. 173°-176°C. C₂₄ H₃₄ N₂ O₇(462.55)

Calculated: C 62.32; H 7.41; N 6.05; Found: C 62.14; H 7.30; N 5.87.

6.3r-(N-Methyl-N-tetramethylene-ammonium)-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)-iodide

25.9 g. (0.1 mole) of I, 38 g. of 1,4-diiodobutane, and 25 g. ofN-ethyl-diisopropylamine are heated together to 100°C. Subsequently themixture is stirred for 1 hour at 125°C. The reaction product isextracted twice with boiling toluene, the residue taken up inchloroform, and this solution is washed with aqueous ammonia and water.After distilling off the chloroform, the residue is recrystallized fromisopropanol.

Yield: 4.5 g. (10%). M.P. 153°-156°C. C₂₀ H₂₈ NIO₂ (441.36)

Calculated: C 54.42; H 6.40; I 28.75; N 3.18; Found: C 54.74; H 6.27; I28.78; N 3.52.

7.3r-(N-Methyl-N-capryloyl-amino)-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

To a solution of 25.9 g. (0.1 mole) of I and 22 g. ofN-ethyl-diisopropylamine in 300 ml. of toluene 17 g. of capryloylchloride are added dropwise at a temperature not exceeding 30°C. After 2hrs. the mixture is stirred for 30 min. at 60°C. The product is washedtwice with 2 N hydrochloric acid and once with water, then dried andconcentrated at 100°C, 0.4 torr. The residue is analytically pure.

Yield: 32.5 g. (84%). An almost colorless, undistillable oil. C₂₄ H₃₅NO₃ (385.55)

Calculated: C 74.77; H 9.15; N 3.63; Found: C 74.90; H 9.24; N 3.74.

8.3r-[N-Methyl-N-(4'-chlorobenzoyl)-amino]-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

To a solution of 25.9 g. (0.1 mole) of I and 16 g. ofN-ethyl-diisopropylamine in 700 cc. of toluene, 17.5 g. (0.1 mole) ofp-chlorobenzoyl chloride, dissolved in 50 cc. of toluene, are addeddropwise, at +5°C. The mixture is allowed to warm to room temperature,and subsequently it is heated for 1 h. to 70°C. The reaction solution isextracted with 2 N hydrochloric acid and water. The residue of thetoluene phase is recrystallized from ethanol.

Yield: 30.1 g. (76%). M.P. 175°-177°C. C₂₃ H₂₄ ClNO₃ (397.91)

Calculated: C 69.42; H 6.08; Cl 8.91; N 3.52; Found: C 69.59; H 6.15; Cl8.95; N 3.54.

9.3r-[N-Methyl-N-(2-carboxyethylcarbonyl-amino]-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

38.8 g. (0.15 mole) of I and 15 g. of succinic anhydride are heated toform a homogeneous melt and kept at 120°C for 3 hrs. The melt is takenup in toluene while hot. The crude product obtained on cooling isrecrystallized from ethanol.

Yield: 34.4 g. (62%). M.P. 132°-133°C. C₂₀ H₂₅ NO₅ (359.43)

Calculated: C 66.83; H 7.01; N 3.90; Found: C 66.93; H 7.06; N 3.90.

10.3r-[N-Methyl-N-(2'-amino-benzoyl)-amino]-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

25.9 g. (0.1 mole) of 1 are heated to 140°C, and 0.1 mole of isatoicanhydride is introduced in several portions. The mixture is kept at thistemperature for 2 hrs. and subsequently taken up in toluene while hot;then the toluene phase is extracted with 0.5 N hydrochloric acid andwith 0.5 N sodium hydroxide solution. After being dried, the organicphase is evaporated under vacuum, and the residue crystallized withisopropanol.

Yield: 5.0 g. (13%) from a mixture of isopropanol and diisopropylether.M.P. 138°-140°C. C₂₃ H₂₆ N₂ O₃ (378.47)

Calculated: C 72.98; H 6.93; N 7.40; Found: C 72.95; H 6.78; N 7.38.

11.N,N'-Dimethyl-N,N'-di[Nr(4c-phenyl-4t-ethoxycarbonyl-cyclohexene-1-yl-3)]succinamide

To 38.8 g. (0.15 mole) of I and 33 g. of N-ethyldiisopropylamine,dissolved in 600 cc. of toluene, 12 g. of succinic dichloride are addeddropwise at 5°-10°C. The solution is stirred for several hours at roomtemperature and subsequently heated to 90°-100°C for 2 hrs. On cooling aprecipitate is formed, which is then suspended in 0.5 N hydrochloricacid and recrystallized from isopropanol. The yield (including theproduct obtained from the toluene mother liquor) amounts to 35.4 g.(78%). M.P. 196°-198°C. C₃₆ H₄₄ N₂ O₆ (600.77)

Calculated: C 71.97; H 7.38; N 4.66; Found: C 72.06; H 7.42; N 5.80.

12.N,N'-Dimethyl-N,N'-di[Nr-(4c-phenyl-4t-ethoxycarbonyl-cyclohexene-1-yl-3]oxamide

To a solution of 38.8 g. (0.15 mole) of I and 30 g. of triethylamine in800 cc. of toluene 0.075 mole of oxalic dichloride is added dropwise, at0° to 5°C. After stirring for 1 hour at room temperature, theprecipitate is separated, taken up in chloroform, washed with 2 Nhydrochloric acid and finally with water. The residue on distillation isrecrystallized from N-butanol.

Yield: 7.7 g. (16%). M.P. 253°-255°C. C₃₄ H₄₀ N₂ O₆ (572.71)

Calculated: C 71.30; H 7.04; N 4.89; Found: C 71.25; H 6.95; N 4.86.

13.3r-(N-Methyl-N-carbamyl)-amino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

To 13 g. (0.05 mole) of I, dissolved in a mixture of 24 ml. of glacialacetic acid and 20 ml. of water, a solution of 8 g. of potassium cyanatein 10 ml. of water is added at 30°C. The mixture is heated for 45 min.to 70°C, poured into water, and extracted with chloroform. The organicphase is extracted with 2 N HCl and with water. After drying the phaseand evaporating, the residue is recrystallized from toluene.

Yield: 2.6 g. (17%). M.P. 142°-144°C. C₁₇ H₂₂ N₂ O₃ (302.38)

Calculated: C 67.52; H 7.33; N 9.27; Found: C 67.56; H 7.42; N 9.31.

14.3r-[N-Methyl-N-(ethylcarbamyl)]-amino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

0.025 mole of ethylisocyanate and 0.025 mole of I are united in 30 ml.of dioxane and heated for 5 hrs. to 30°C. The residue of the dioxanephase is recrystallized from aqueous isopropanol.

Yield: 5.3 g. (64%). M.P. 140°-141°C. C₁₉ H₂₆ N₂ O₃ (330.43)

Calculated: C 69.06; H 7.93; N 8.48; Found: C 69.34; H 7.78; N 8.19.

15.3r-[N-Methyl-N-(butylcarbamyl)]-amino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

This compound is prepared from butylisocyanate and I, as in example 14.

M.p. 117°-118.5°c. recrystallized from isopropanol. C₂₁ H₃₀ N₂ O₃(358.49)

Calculated: C 70.35; H 8.44; N 7.82; Found: C 70.27; H 8.26; N 8.02.

16.3r-[N-Methyl-N-(2'-carboxy-phenyl-carbamylamino)]-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

51.8 g. (0.2 mole) of I and 0.15 mole of isatoic anhydride are heated in250 cc. of DMF for 3 hrs. to 110°-20°C. The solvent is distilled off,and after being taken up in toluene the residue is extracted with 500cc. of 0.5 N hydrochloric acid. This results in the precipitation of theproduct according to 16.

Yield: 21.8 g. (34%). M.P. 187°C (decomposition) from isopropanol. C₂₄H₂₆ N₂ O₅ (422.48)

Calculated: C 68.22; H 6.21; N 6.63; Found: C 68.22; H 6.31; N 6.31.

The analgesic effectiveness and LD₅₀ of representative compoundsproduced by the process of the present inventions were demonstrated inthe following tests.

The LD₅₀ values were determined using male and female rats with weightsin the range of 90 to 120 grams:

3r-N-monomethylamino-4-c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

In a test of 12 animals, LD₅₀ was determined to be 250 mg/kg whenadministered subcutaneously and the LD₅₀ in intragastric administrationwas 550mg/kg.

This same compound demonstrated analgesic activity using thephenyl-p-quinone writhing test. Twelve out of twelve rats were protectedfrom sensitivity from pain at a dosage level of 11.25 mg/kg. Thecompound in this case was administered subcutaneously.

3r-(N-methyl-N-ethyl-amino)-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)

The LD₅₀ in the form of an Armstrong salt using the method as above, wasdetermined to be 1600 mg/kg when administered intragastrically.

The LD₅₀ of this compound in the form of its oxalate salt was 453 mg/kgadministered intragastrically.

In the Randall-Selitto test the following values have been obtainedadministering the compound in water intragastrically in a dosage of 100mg/kg.

Control animals are in pain at a load of 148 g. Animals having 100 mg/kgof amidopyrine are in pain at a load of 212 g. Animals treated with thecompound of the invention are in pain at a load of 352 g.

Having described our invention, we claim:
 1. A process for theproduction of N-alkyl and N-aminoalkyl of the formula: ##SPC4##in whichR represents a lower alkyl of 1-7 carbons or an amino substituted loweralkyl of 1-7 carbons, said process comprising treatment of3r-N,N-dimethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1)##SPC5## with bromine in chloroform at -15° to 0°C. followed bytreatment of the brominated product with water and reacting the3r-N-monomethylamino-4c-phenyl-4t-ethoxycarbonyl-cyclohexene-(1) soproduced and of the formula: ##SPC6## with one equivalent of lower alkylhalide or lower alkyl sulfate, lower alkyl being defined as having 1-7carbons, at 70° - 130°C in a suitable solvent or in the absence of asolvent in the presence of at least one equivalent ofN-ethyl-diisopropylamine.